Recently, a brain disease issues a national burden in Korea. The brain disease has taken the most dramatic increase as a cause of death in the past 10 years, but it is expected that the damage of the disease should increase rather than other diseases due to the difficulty in diagnosis and treatment.
In particular, dementia causes whole mental malfunctions such as memory impairments and a loss of skills to think, thereby ruining human life. There are various causes of dementia. 50 percent are Alzheimer's disease typed dementia, 20-30% are vascular dementia, alcoholic dementia or Parkinson's disease typed dementia, etc. and about 15-20% are Alzheimer's Disease and vascular dementia.
Alzheimer's disease (hereinafter, ‘AD’)-associated dementia is also called as senile dementia and starts mostly at forties. Its cause has net been exactly proven, but is revealed to closely relate with the aging.
The dementia has been reported to be caused by nervous cell damage or the decrease of acetylcholine concentration. The nervous cell damage is induced by various causes such as free radical, glutamate, excessive calcium, nitrogen, beta-amyloid protein, cytokine and the like. The nerve cell of patient with Alzheimer's disease represents neuritis plaque including excessive amount of beta-amyloid (β-Amyloid). The beta-amyloid is formed from amyloid precursor protein (hereinafter, ‘APP’) and produces P3 amyloid from amyloid precursor protein in normal human.
However, in case of the Alzheimer's disease, there are two hallmark disease patterns of amyloid plaque made up of beta-amyloid protein in outer part of nerve cell, and the neurofibrullary tangle (inside of nerve cell) composed of over-phosphorylated tau protein playing a crucial role in the structure of the neuron and the neurotransmission.
The excessive formation of beta-amyloid may be a representative step of starting a neurodegenerative brain disease. The aggregates of beta-amyloid in brain are considered as various toxicity in nerve cell causing neuritis plaque
In vitro and in vivo experiments, the neurotoxicity of the beta-amyloid was proven to induce nerve cell apoptosis. For example, when neuron in cultured central nervous systems and nerve cell PC12 was exposed to beta-amyloid, beta-amyloid induced nerve cell apoptosis (Loo et al., Proc Natl Acad Sci USA, 1993, 7951-7955; Ivins et al., J Bio Chem, 1999, 2107-2112). beta-amyloid increased notably neurotoxicity in mesencephalic and cortical neuron in the presence of microglia. The activation of microglia and the formation of peroxide free radical increased the toxicity in nerve cell. (Gao et al., J. Neurochem., 2002, 1285-1297; Qin et al., Neurochem., 2002, 973-983). The brain inflammation has been widely recognized as an important cause of various neurodegenerative brain diseases including Parkinson's disease, Alzheimer's disease and the like. The inflammation-mediated degeneration of nerve cell occurs with the activation of microglia which produces various effective factors for degenerating a neuron such as eicosanoids, cytokine, reactive oxygen species, nitrogenoxide, etc. (Qin et al., Neurochem., 2002, 973-983) In previous studies, the relationship between the beta-amyloid-dependent activation of microglia and various characteristics markers of neuron apoptosis in brain of patient suffered from Alzheimer's disease (Combs et al., J Neurosci., 2001, 1179-1188).
Interestingly, beta-amyloid had highly-increased neurotoxicity in both of mesencephalic and cortical neuron in the presence of microglia (Gao et al., J Neurochem., 2002, 1285-1297; Qin et al., Neurochem., 2002, 973-983). Accordingly, APP may be accompanied with pathogenesis of other neurodegenerative brain diseases such as Parkinson's Disease as well as Alzheimer's disease (Puglielli and Kovacs, Rev Med. Chil., 2001, 569-575; Small et al., Nature Rev., 2001, 595-598). Parkinsonism symptoms also occur in a patient with Alzheimer's disease generally, and cognitive decline in patient with Alzheimer's disease was related with progression of Parkinsonism (Wilson et al., Psychol Aging, 2000, 18-28). Because dopamine neuron are known to be weak for the oxidative stress (Greenamyre et al., Biochem Soc Symp 1999, 85-97), the inhibition of microglia activation can be effective strategy for developing potential drug.
Accordingly, in the prevention and treatment of neurodegenerative brain disease, there are need to search and develop materials for inhibiting beta-amyloid and microglia activation.